There is a kind of a barrier present in the neural tissue that prevents particular materials from entering the blood vessels. This functional barrier is called blood-brain barrier (BBB, or blood-brain portal). Blood-brain barrier brain capillaries are capable of maintaining homeostasis of the microenvironment of neurons and are highly differentiated. The blood-brain barrier is a structure formed to maintain the transport of unnecessary materials at the minimum level due to a lower blood vessel permeability being maintained by the capillaries present in the neural tissue, compared to other tissues. The main structure establishing the blood-brain barrier consists of tight junctions or zonula occluden in the capillary endothelial cells. The fenestra, which is frequently seen in the capillaries of various other regions, is not present in the cytoplasm of the endothelial cells, and a pinocytotic vesicle is also present very rarely. Low molecular weight materials which are necessary for the neural tissue bind to carriers present in the cytoplasm and enter the brain parenchyma. Since the blood-brain barrier blocks the unspecific entry of ions, proteins, and other materials into the environment of central nervous system, the role as such a barrier enables the protection of neurons from harmful components being supplied from the blood while allowing essential materials to permeate therethrough. Most brain injuries such as cerebral infarction and trauma are associated with the disruption of the blood-brain barrier, and this in turn causes a secondary injury of neurons. Accordingly, the studies on the mechanism of generation and control of the blood-brain barrier are very important for the understanding and treatment of central nervous system diseases. Additionally, many kinds of drugs and metabolites cannot penetrate the blood-brain barrier, and thus an appropriate control of the blood-brain barrier can be very important for the administration of the drugs into the desired place in the treatment of various brain diseases including dementia.
In general, the blood-brain barrier may be considered as an organ to serve the role of protecting brain homeostasis. A blood-brain barrier disorder is associated with brain disorders. For example, vascular cerebral edema is the most common form of cerebral edema and it occurs due to the increase of permeability of capillaries. As the blood-brain barrier becomes loose due to a certain reason, the permeability to the blood serum proteins increases and the blood plasma filtrate leaks out through the intercellular space thereby causing cerebral edema. This is the major cause of dysfunction and death with symptoms such as seizure, brain infection, head injury, brain tumor, and multiple sclerosis. Additionally, multiple sclerosis causes activated autoreactive T cells to penetrate the blood-brain barrier. In the CNS, the above T cells induce a targeted inflammation response with respect to the myelin sheath and induce the disruption of the blood-brain barrier, autoantibodies and complement factors are introduced into the disrupted blood-brain barrier, thereby causing a demyelination process. Additionally, when the balance is broken in the neurotransmitters and minute ions in the extracellular fluid, it damages neuronal signaling, and subsequently the damage in the functionalization of recognition, neuropsychiatric impairment, or epileptic seizure. Additionally, impaired removal of damaged toxic proteins over the entire blood-brain barrier into the bloodstream has recently been proposed as a cause of neurodegenerative disorders such as Alzheimer's disease and prion diseases such as Creutzfeldt-Jakob disease and BSE. Accordingly, treatment of the functional disorder of the blood-brain barrier is suggested as a new solution to the treatment of brain disorders.
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, and is used to treat depression, obsessive compulsive disorders, bulimia nervosa, anorexia nervosa, and panic disorders. Regarding the effects of fluoxetine other than as an antidepressant, it was reported to increase the anticonvulsive effect of carbamazepine, phenytoin, and ameltolide in the maximum electroconvulsive shock test using mice (Leander, J. D., 1992, Epilepsai 33: 573-576), and increase the effect of an antiepileptic agent co-administered with fluoxetine, and thus it was reported that fluoxetine can be useful for the treatment of depression patients with epilepsy. Recently, fluoxetine was reported to have an anti-inflammatory effect after ischemic injury and thus can be used for the protection effect of neurons (Lim, C. M. et. al, 2009, J. Neurosci. Res. 87, 1037-1045), and fluoxetine was also reported to inhibit the activity of matrix metalloproteinase (MMP) after spinal cord injury thereby being capable of preventing the disruption of blood spinal cord barrier (Lee, J. Y. et al, 2012, Brain 135, 2375-2389).
Vitamin C is one of trace elements necessary for the maintenance of functions and health of the human bodies and is also called ascorbic acid. Vitamin C helps human bodies to resist infections, heals injuries, helps to maintain tissues, and as one of antioxidants, is known to prevent cell damage by free radicals. Regarding the treatment of disruption of the blood-brain barrier and sensory defect, it was previously reported that vitamin C has the effect of alleviating the injuries in blood-brain barrier and sensory neurons induced by continuous compression (J-L Lin et al, 2010, jcbfm 30, 1121-1136). However, there has been no report regarding the effect of fluoxetine and vitamin C on the alleviation of the injury of blood-brain barrier.